Pharmaceutical compositions containing nifedipine and process for the preparation thereof

ABSTRACT

This invention relates to a slow release nifedipine-containing pharmaceutical compositions and methods of making such compositions. The compositions of the inventions comprise a soluble carrier coated with nifedipine and polyvinylpyrrolidone and an acrylic based polymer. Nifedipine is present, in amorphous form, in excess amounts to polyvinylpyrrolidone and in equal or excess amounts to the acrylic based polymer.

INTRODUCTION

This introduction is a 371 of PCT/GB93/00055, filed Jan. 12, 1993, andpublished as WO93/13773 Jul. 22, 1993.

1. Technical Field

The present invention relates to pharmaceutical compositions containingnifedipine and to a process for the preparation thereof. In particularthe present invention relates to a slow release pharmaceuticalformulation containing nifedipine which provides for a regular andprolonged release pattern upon administration and, in its most preferredform, may be administered once a day. The invention also relates to aprocess for the preparation thereof.

2. Background to the Invention

The drug nifedipine is currently used in the form of rapid release andcomparatively slow release pharmaceutical dosage forms for thetreatment, respectively, of acute angina and chronic hypertension. Itappears that, for the acute treatment of angina, it is desirable quicklyto attain relatively high nifedipine concentrations in plasma and thisrequirement is currently served by a preparation consisting of asolution of nifedipine in low molecular weight polyethylene glycolcontained within soft gelatin capsules. For the treatment ofhypertension it appears that it is more desirable to maintain plasmanifedipine concentrations within a much lower concentration range.Modified release preparations of the substance are available for thispurpose, although they mostly still require multiple daily doses to betaken which is both a clinical disadvantage in that symptomatic controlof the condition may not be optimised and a disadvantage from thepatient's point of view. The inconvenience of taking a dosage more thanonce per day may affect compliance with the dosage regime, also leadingto poor clinical performance.

The reason for the two significantly different types of formulation isthat nifedipine per se is very poorly soluble in water. Because of thismany of the patent specifications on controlled release systems ofnifedipine describe means of actually enhancing, rather thansuppressing, the solubility of nifedipine.

Thus, in European Patent No. 0047899 (corresponding to Canadian PatentNo. 1180277) control of the dissolution of nifedipine is achieved byprocessing the material to give it a large specific surface area of 0.5to 6m² /g. The specification discloses the production of fine nifedipinecrystals by grinding and screening but not by any other means.

Similarly, in PCT/EP85/00481 the control of nifedipine dissolution isachieved by limiting its specific surface area to 0.1 to 0.42m² /g andcoating the nifedipine crystals, in admixture with an equal quantity ofa filler, onto inert spheroids by means of suitable binders.

Further enhancement of the dissolution of nifedipine is achieved byprocessing the material to form a solution adsorbed onto a solid base(as in British Patent No. 1,456,618), or to form a solid solution (alsoknown as a co-precipitate) with high molecular weight polyethyleneglycol (European Patent Application No. 0220760) or an ester or ether ofpolyethylene glycol (European Patent Application No. 0249587) or withother selected materials, including polyvinylpyrrolidone (British PatentNo. 1,579,818).

This ability of polyvinylpyrrolidone to enhance the solubilitycharacteristics of certain materials by forming coprecipitates with themis now fairly well documented. It is also generally accepted that inorder to form such coprecipitates the amount of polyvinylpyrrolidoneused must be in excess of the amount of active material.

In our European Patent No. 385582 we describe pharmaceuticalcompositions in which polyvinylpyrrolidone in an amount less than theamount of nifedipine actually significantly slows the dissolution ofnifedipine from the finished solid dosage form. More specifically, EP385582 discloses a pharmaceutical composition which comprises particlesof a finely divided pharmaceutically acceptable water soluble carriercoated with microparticles of nifedipine, the majority of which have aparticle size of 100 micrometers or less, in the presence ofpolyvinylpyrrolidone, the polyvinylpyrrolidone being present in anamount of from 10 to 90% by weight based on the weight of thenifedipine.

We have found that these compositions can provide a slow release ofnifedipine over a period of up to about 12 hours, i.e. to provide apotential composition for twice-daily administration of nifedipine.Attempts to slow the release of nifedipine from the tablets byincreasing the amount of polyvinylpyrrolidone were unsuccessful and theaddition of other materials to the system diluted the effect ofpolyvinylpyrrolidone and thus only succeeded in speeding the release ofnifedipine from the compositions.

Acrylic resins have previously been used in tablet compositions.However, they have been used in much larger relative amounts than in thepresent invention, and the resulting compositions have short releaseprofiles.

GB 2229095 describes compositions containing nifedipine in crystallineform, hydrophilising agent and retarding agent. Polyvinylpyrrolidone ismentioned as a hydrophilising agent, but no example is given. Forsustained release composition, the amount of retarding agent required isin the range 0.2 to 1.5 parts by weight relative to the nifedipinecontent. In this document, polyvinyl butyrate is preferred as theretarding agent because a smaller amount is said to be required than ifan acrylic polymer is used.

In WO86/01717 nifedipine is coated by spraying onto sucrose granuleswhich have first been wetted with polyvinylpyrrolidone. The coatedgranules are then wetted with Eudragit (an acrylic polymer) in a ratioof 35 parts by weight Eudragit to one part by weight of nifedipine.

Sugimoto et al. in Drug Development and Industrial Pharmacy (1980), 6,p137-160 and Chem. Pharm. Bull (1982) 30 (12) p4479-2288 discuss the useof polymeric materials to increase the solubility of PVP inco-precipitates, resulting in nifedipine formulations with rapid releasecharacteristics. Where PVP is mentioned, the amount of PVP used in theco-precipitates of nifedipine with PVP is always in amounts in excess ofthe nifedipine content.

SUMMARY OF THE INVENTION

There is a need for a potential product for once-daily administration ofnifedipine. We have surprisingly discovered that the addition of anacrylic resin to certain pharmaceutical compositions, for example thosedisclosed in our earlier European Patent No. 385582 results incompositions that can become useful as once a day treatments.

The present invention provides a pharmaceutical composition whichcomprises particles of a finely divided pharmaceutically acceptablewater soluble carrier coated with a mixture of nifedipine withpolyvinylpyrrolidone or a copolymer of N-vinyl-pyrrolidone and vinylacetate, and a pharmaceutically acceptable acrylic based polymer, theweight ratio of the polyvinylpyrrolidone or copolymer ofN-vinylpyrrolidone and vinyl acetate copolymer to the content ofnifedipine being in the range of from 1:1 to 1:10 and the weight ratioof the acrylic based polymer to the content of nifedipine being in therange of from 1:4 to 1:20.

The present invention also includes within its scope a process for thepreparation of the pharmaceutical compositions as defined above, whichprocess comprises forming a solution of nifedipine, polyvinylpyrrolidoneor a copolymer of N-vinylpyrrolidone and vinyl acetate and apharmaceutically acceptable acrylic based polymer (which may for examplebe an acrylic resin) in a suitable solvent, coating particles of afinely divided pharmaceutically acceptable water soluble carrier whichis insoluble in the solvent with the solution and evaporating thesolvent from the surface of the coated carrier particles.

Throughout the present specification the copolymer of N-vinylpyrrolidoneand vinyl acetate will be referred to as an "N-vinylpyrrolidonecopolymer". A suitable example of such a copolymer is Kollidon VA 64obtainable from BASF.

All ratios are by weight. Preferably, the ratio of the acrylic basedpolymer to the content of nifedipine is in the range 1:5 to 1:12. Mostpreferably this ratio is in the range 1:6 to 1:10.

It is further preferable that the ratio of the content ofpolyvinylpyrrolidone or N-vinylpyrrolidone copolymer in the compositionto the content of nifedipine is in the range 1:2 to 1:8. Very preferablythis ratio is in the range 1:2 to 1:5. A particularly advantageous ratiois 1:4.

In a highly preferred form of the invention the nifedipine is present ina predominantly amorphous form in the composition. We believe that thecomposition is a highly amorphous layer of a solid solution ofpolyvinylpyrrolidone (or N-vinylpyrrolidone copolymer), nifedipine andacrylic based polymer coated on the carrier, as distinct from thenifedipine being in crystalline form. However, the invention is not bebe limited by theoretical considerations and the possibility is notexcluded that some of the nifedipine may have some crystallinestructure.

In our own SEM (scanning electron microscope) studies, no crystallinenifedipine was seen.

Preferably the amount of drug released from a composition according tothe invention in an in vitro dissolution test is related to time by alinear relationship better than by a square-root of time relationship.

Advantageously, dosage units formed from a composition of the inventioncan provide substantially linear release of nifedipine over 8 hours, ormore.

DESCRIPTION OF SPECIFIC EMODIMENTS

The pharmaceutically acceptable water soluble carrier may be any carrierwhich is normally used in the preparation of pharmaceuticalcompositions, for example lactose, sucrose, mannose, sorbitol, ormixtures thereof. The pharmaceutically acceptable water soluble carrierpreferably has a particle size of less than 250 micrometers andpreferably also has a specific surface area of greater than 0.5 m²/gram.

Although polyvinylpyrrolidone and N-vinylpyrrolidone copolymer are knownas binders for use in the preparation of various pharmaceuticalcompositions, these materials have, when used in the proportions hereinspecified and incorporated together with the acrylic based polymer inthe manner described, a specific effect in controlling the rate ofdissolution and release of nifedipine from the coated carrier particles.

The pharmaceutically acceptable acrylic based polymer which isincorporated into the pharmaceutical compositions of the presentinvention may be any suitable pharmaceutically acceptable acrylic basedpolymer. By acrylic based polymer we mean a polymer whose monomer unitsare primarily or entirely acrylic or allylacrylate. Low amounts e.g. upto 10% by weight of co-monomer may be present. The acrylic based polymermay be cationic, non-ionic or anionic and may be, for example, apoly-acrylate, a poly-methacrylate or a copolymer of acrylic andmethacrylic acid esters. Any of these may have a low content ofquaternary ammonium groups. Non-ionic acrylic based polymers are highlypreferred, as are acrylic resins. Examples of suitable acrylic basedpolymers are the whole of the range sold under the trade name EUDRAGITBY Rohm Pharma GmbH.

In carrying out the process of the present invention, the water solublecarrier may be coated with the nifedipine/polyvinylpyrrolidone/acrylicbased polymer in a single stage process or in a stepwise manner. Forexample, all of the solution may be coated onto the carrier in one stageor, alternatively and preferably, part of the solution may be coatedonto the carrier and the mixture granulated and dried, followed bycoating of the dry granulate with the remaining part of the solution anddrying and granulating the resulting mixture. This stepwise process maybe performed in more than two steps.

The solvent which is used in the process of the invention must be asolvent for nifedipine, the polyvinylpyrrolidone and the acrylic basedpolymer, but should not dissolve the pharmaceutically acceptablecarrier. Examples of suitable solvents are lower aliphatic alcohols,methylene chloride or chloroform. The most preferred solvent for use ischloroform.

The solvent evaporates from the surface of the coated carrier particlesthus leaving nifedipine in the presence of the polyvinylpyrrolidone andthe acrylic based polymer, coated onto the particles of the finelydivided pharmaceutically acceptable water soluble carrier. As mentioned,it is preferred that in this coating the nifedipine shows amorphous,rather than crystalline, characteristics.

The pharmaceutical composition of the present invention may beformulated into a solid unit dosage form, such as tablets or capsules,in a conventional manner. In the preparation of such formulationsconventional additives may be used such as lubricants, binders,stabilizers etc.

The pharmaceutical compositions of the present invention possess goodstability and are easily reproducible. During the preparation of thecompositions milling is not required and this avoids the formation ofnifedipine dust.

It will be appreciated that dry milling techniques are tedious andexpensive and, furthermore, that the dust from a drug such as nifedipineis potentially hazardous. The process of the present invention thusprovides an economic and simple route to the production of apharmaceutical composition comprising nifedipine.

The present invention will be further described with reference to thefollowing Examples and the accompanying drawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the rate of release of nifedipine in in vitrodissolution tests from the tablets of Examples 1 to 4;

FIG. 2 illustrates mean blood levels of nifedipine attained afteradministration to human volunteers of one tablet as described in Example3 in comparison with two other compositions; and

FIGS. 3 to 5 are SEM photomicrographs of granules according To Theinvention.

EXPERIMENTAL

A. General Processing Method

Nifedipine and polyvinylpyrrolidone (PVP) were dissolved in chloroform(nominal quantity of 0.15 ml chloroform per tablet containing a nominalcontent of 30 mg nifedipine) and mixed using a propeller mixer. Acrylicresin (Eudragit RS 100) was dissolved in the resulting solution andmixed for ten minutes.

Lactose was placed in a mixer granulator and granulated with half of thenifedipine/acrylic resin solution. Mixing was continued for one minuteafter the addition of the solution at which time the mixer was stopped,the bowl scraped down, the mixer re-started and the wet granulate mixedfor a further four minutes. The resulting wet granulate was fluid beddried for fifteen minutes at an air inlet temperature of 60° C.

Dry first-stage granulate was returned to the mixer/granulator andregranulated with the remaining nifedipine/acrylic resin solution andthe resulting granulate mixed for one minute. The mixer was stopped, thesides of the bowl scraped down, the mixer re-started and the wetgranulate mixed for a further four minutes. The resulting wet granulatewas fluid bed dried for ten minutes at an air inlet temperature of 60°C.

The resulting dry granulate was screened through a 1 mm aperturestainless steel sieve and fluid bed dried at an air inlet temperature of60° C.

Appropriate amounts of hydrogenated castor oil and purified talc to beemployed as lubricant were added to the dry granulate and blended in aY-cone blender for ten minutes.

The resulting lubricated granulate was compressed into tablets.

EXAMPLE 1

Preparation of composition containing acrylic polymer and nifedipine ina weight ratio of 1:12

Using the general procedure detailed in A above tablets were preparedeach having the following composition:

    ______________________________________                                                          Parts by Weight                                             ______________________________________                                        Nifedipine          30.0                                                      Polyvinylpyrrolidone                                                                              7.5                                                       Lactose             300.0                                                     Acrylic Polymer (Eudragit RS)                                                                     2.5                                                       Hydrogenated Castor Oil                                                                           3.5                                                       Purified Talc       7.1                                                       ______________________________________                                    

In vitro dissolution tests were carried out using the USP DissolutionTest Apparatus 2, employing a paddle speed of 50 rpm, operated at 37° C.with 2.5% w/v aqueous sodium dodecylsulphate solution used as thedissolution test medium.

The rate of release of nifedipine from these tablets in thesedissolution tests is plotted in FIG. 1.

EXAMPLE 2

Preparation of composition containing acrylic polymer and nifedipine ina weight ratio of 1:8.57

Using the general procedure detailed above in A tablets were preparedeach having the following composition:

    ______________________________________                                                          Parts by Weight                                             ______________________________________                                        Nifedipine          30.0                                                      Polyvinylpyrrolidone                                                                              7.5                                                       Lactose             300.0                                                     Acrylic Polymer (Eudragit RS)                                                                     3.5                                                       Hydrogenated Castor Oil                                                                           3.5                                                       Purified Talc       7.1                                                       ______________________________________                                    

Dissolution tests were carried out according to the procedure of Example1 and the results are plotted in FIG. 1.

EXAMPLE 3

Preparation of composition containing acrylic polymer and nifedipine ina weight ratio of 1:6.67

Using the general procedure detailed above in A tablets were preparedeach having the following composition:

    ______________________________________                                                          Parts by Weight                                             ______________________________________                                        Nifedipine          30.0                                                      Polyvinylpyrrolidone                                                                              7.5                                                       Lactose             300.0                                                     Acrylic Polymer (Eudragit RS)                                                                     4.5                                                       Hydrogenated Castor Oil                                                                           3.5                                                       Purified Talc       7.1                                                       ______________________________________                                    

Dissolution tests were carried out according to the procedure of Example1B and the results are plotted in FIG. 1.

EXAMPLE 4

Preparation of composition containing acrylic polymer and nifedipine ina weight ratio of 1:4.7

Using the general procedure detailed above in A tablets were preparedeach having the following composition:

    ______________________________________                                                          Parts by Weight                                             ______________________________________                                        Nifedipine          30.0                                                      Polyvinylpyrrolidone                                                                              7.5                                                       Lactose             300.0                                                     Acrylic Polymer (Eudragit RS)                                                                      6.38                                                     Hydrogenated Castor Oil                                                                           3.5                                                       Purified Talc       7.1                                                       ______________________________________                                    

Dissolution tests were carried out according to the procedure of Example1 and the results are plotted in FIG. 1.

Table 1 presents the dissolution test data of examples 1 to 4 in tableform, and shows the dissolution profile over a slightly longer periodthan does FIG. 1. The table also gives the time to 50% release (T₅₀) foreach formulation. The T₅₀ values of these compositions show that theyare useful once-a-day preparations. In particular the formulations ofExamples 2 and 3 with T₅₀ values of around 7 hours are very useful.

EXAMPLE 5

Preparation of composition containing acrylic polymer and nifedipine ina weight ratio of 1:7.5

Using the general procedure detailed above tablets were prepared eachhaving the following composition:

    ______________________________________                                                          Parts by Weight                                             ______________________________________                                        Nifedipine          30.0                                                      Polyvinylpyrrolidone                                                                              7.5                                                       Lactose             300.0                                                     Acrylic Polymer (Eudragit RS)                                                                     4.0                                                       Hydrogenated Castor Oil                                                                           3.5                                                       Purified Talc       7.1                                                       ______________________________________                                    

Tablets of this Example were used in a test described below.

                  TABLE 1                                                         ______________________________________                                        Time (h)                                                                              Example 1 Example 2 Example 3                                                                             Example 4                                 Dissolution test profile:                                                     mean percentage released from 6 replicate tables at time                      ______________________________________                                        (hour)                                                                        1.0                          7       4                                        1.5     16        10                                                          2.0                         15       6                                        3.0     31        18        22      10                                        4.0                         28      14                                        4.5     48        29                                                          5.0                         35      19                                        6.0     70        42        45      24                                        7.0                         52      32                                        7.5     84        57                                                          8.0                         62      37                                        9.0               73                                                          10.0                        77                                                10.5              85                                                          12.0                        86                                                16.0                                80                                        17.0                                85                                        T.sub.50 **                                                                             4.6       6.8       6.8     11.4                                    ______________________________________                                         **T.sub.50 = Time to 50% release                                         

The in vitro dissolution procedure used in these tests has been shown togive results that correlate very satisfactorily with in vivo resultsover a wide range of release rates.

EXAMPLE 6

Table 2 below shows the results of in vitro dissolution tests carriedout as in Examples 1-4 on three development scale batches withpolyvinylpyrolidone and nifedipine in weight ratios of 1:7.9, 1:4 and1:2.7. The acrylic polymer (Eudragit RS) in each batch formulation wasin a weight ratio of 1:6.67 with respect to nifedipine. Batch No. 2 wasequivalent to the formulation in Example 3.

    ______________________________________                                        Batch No.  1            2      3                                              PVP:N ratio                                                                              1:7.9        1:4    1:2.7                                          time (h)   % nifedipine released                                              ______________________________________                                          0.25      2            2      1                                               0.5       3            4      4                                             1           8            7      5                                             2          13           13     11                                             3          21           21     16                                             4          30           26     22                                             5          36           33     26                                             6          42           40     29                                             7          49           48     33                                             8          55           57     39                                             ______________________________________                                    

RELEASE CHARACTERISTICS

We found that the profile of drug release from compositions according tothe present invention closely follows zero-order kinetics. This is incontrast to the prior art products for which the profile is non-lineardue to diffusion controlled release of drug. The linear release profilehas a significant advantage because a steady rate of supply of drug tothe body will result in relatively steady blood levels. In the treatmentof chronic heart conditions with nifedipine this is especiallyadvantageous. Furthermore, the side-effects associated with The use ofnifedipine may be reduced since these are often associated with peaks inthe level of nifedipine in the blood.

Statistical analyses of release data from batches of tablets subjectedto the in vitro dissolution rest show that the pattern of drug releasefrom tablets according to the present invention follows substantiallyzero-order release kinetics. In other words, the relationship betweenthe amount of drug released and time is linear. This means that theamount of drug available for absorption is fairly constant over a periodof time.

The release data from individual replicate tablets is modelled accordingto the equations representing:

(a) the linear relationship of the amount of drug released (Q) as afunction of time (t) in the in vitro dissolution test (Qαt) and

(b) the relationship between the amount of drug released (Q) and thesquare root of time (√t) in the in vitro dissolution test (Qα√t) fromstart up to a level of at least 70% release from the product in eachcase.

1. The relative goodness of fit of the experimental results to each ofthe models is assessed by Pearson's product moment correlationcoefficient (r value) for each individual tablet tested.

2. Each r value is transformed to `Fisher's Z` value by calculation asfollows: ##EQU1##

3. The replicate values of `Z` obtained from the individual tabletdissolution results from the linear and square-root of timerelationships are then compared using standard parametric statisticalprocedures, for example, two sample t tests or the one-way analysis ofvariance (ANOVA) test to determine the statistical significance of thedifference of the goodness of fit of the experimental data to each ofthese relationships.

By a linear relationship we mean a relationship in which either or bothof the following conditions is satisfied:

a) the arithmetic mean value of Z from replicate drug release resultsfitted to the linear relationship is greater than the arithmetic meanvalue of Z from the replicate drug release results fitted to thesquare-root of time relationship and/or

b) in the t test (or ANOVA) the significance of the difference(one-tailed) is equal to, or less than, a value of p=0.5.

Such a p value represents the situation where there is at least 95%probability that the fit of the experimental release results to thelinear model is better than that to the square-root of time model.

The results of the statistical analysis on batch data is tabulated below(Table 3). The batches represent a formulation series containingEudragit (as the acrylic based polymer) over a range. They alsorepresent development-scale (3300 tablets) up to production-scale(113000 tablets) manufacture: in each case, the results indicate thatthe goodness of fit of the in vitro release data to the zero-order modelis better than to the square-root of time relationship.

                                      TABLE 3                                     __________________________________________________________________________                   Example 1                                                                           Example 2                                                                           Example 5                                                                           Example 3                                                                           Example 3                                                                           Example 3                                                                           Example                    __________________________________________________________________________                                                       4                          Batch size     3300  113000                                                                              113000                                                                              3300  3300  56800 3300                       (number of tablets)                                                           Content of nifedipine                                                                        30    30    30    30    30    30    30                         (mg/tablet)                                                                   Content of acrylic resin                                                                     2.5   3.5   4.0   4.5   4.5   4.5   6.4                        (mg/tablet)                                                                   Fit to zero-order                                                             relationship:                                                                 r =            0.9973                                                                              0.9970                                                                              0.9968                                                                              0.9967                                                                              0.9921                                                                              0.9990                                                                              0.9960                     Z =            3.2984                                                                              3.2553                                                                              3.2176                                                                              3.2030                                                                              2.7673                                                                              3.8107                                                                              3.1032                     Fit to square-root of time                                                    relationship:                                                                 r =            0.9885                                                                              0.9810                                                                              0.9893                                                                              0.9729                                                                              0.9617                                                                              0.9889                                                                              0.9464                     Z =            2.5779                                                                              2.3222                                                                              2.6126                                                                              2.1440                                                                              1.9678                                                                              2.5958                                                                              1.7958                      ##STR1##      1.28  1.40  1.23  1.49  1.41  1.47  1.73                       Significance of difference                                                                   <0.001                                                                              <0.001                                                                              0.013 <0.001                                                                              <0.001                                                                              <0.001                                                                              <0.001                     between Z zero order/Z sq rt                                                  time:                                                                         p =                                                                           __________________________________________________________________________

The findings show that it is possible to obtain zero-order drug releasefrom the tablets a) over a range of formulations and b) when producingthe tablets either in the laboratory (development-scale batches) or onconventional pharmaceutical production-scale processing plant.

EXAMPLE 7

FIG. 2 illustrates the levels of intact nifedipine, i.e. the drug thathas nor undergone any form of metabolism and which is present in theblood circulation in the chemical form in which it has beenadministered, following single doses of 10 mg of animmediately-releasing formulation (labelled as Imm rel caps), or 30 mgin the form of the tablets of Example 3, or in the form of Procardia XLtablets which is a controlled-release nifedipine product marketed in theUSA as an osmotically regulated device (labelled as osmotic tab 30 mg).

The blood level vs time profile for the product of Example 3 shows thefollowing advantages:

i) it shows a prolongation of nifedipine release and absorption into thebody compared with the immediately releasing product;

ii) it does not suffer from the initial lag-time shown by the productwhich is in the form of an osmotically regulated device, and

iii) it can provide for controlled release of the nifedipine in a mannerwhich suggests the clinical usefulness of the product when administeredonce daily.

EXAMPLE 8

Three sets of granules were manufactured according to (a) Example 2 in asmall batch of 3,000 tablets (set 1), (b) Example 2 in a batch of113,000 tablets (set 2) and (c) Example 3 (except for the drying step)in a batch of 3,300 tablets (set 3). The sets were used in a scanningelectron microscopic study. The granules in set 3 were tray driedinstead of being fluid bed dried.

The granules were mounted and examined using an ISI 100A scanningelectron microscope with an accelerating voltage of 10 kv at a workingdistance of 20 mm.

Three fields for each sample were examined at a magnification of×1250.The results of the magnification in field 1 only are shown in thephotomicrographs of FIGS. 3 to 5 (FIG. 3=set 1, FIG. 4=set 2, FIG. 5=set3). The other two fields gave a similar appearance. All three sets gavethe appearance of standard tablet granules. No nifedipine crystals wereseen in any of the fields of view indicating that nifedipine is presentin a amorphous phase.

I claim:
 1. A slow-release pharmaceutical composition which comprisesparticles of a finely divided pharmaceutically acceptable water solublecarrier coated with a solid solution containing a mixture of nifedipine,polyvinylpyrrolidone or a copolymer of N-vinylpyrrolidone and vinylacetate, and a pharmaceutically acceptable acrylic based polymer, theweight ratio of the polyvinylpyrrolidone or copolymer ofN-vinyl-pyrrolidone and vinyl acetate to the content of nifedipine beingin a range of from 1:1 to 1:10 and the weight ratio of the acrylic basedpolymer to the content of nifedipine being in the range of from 1:4 to1:20.
 2. A composition according to claim 1 wherein said ratio of theacrylic based polymer to the content of nifedipine is in the range 1:5to 1:12.
 3. A composition according to claim 1 wherein said ratio of theacrylic based polymer to the content of nifedipine in the composition isin the range 1:6 to 1:10.
 4. A composition according to claim 1 whereinsaid ratio of the content of the polyvinylpyrrolidone or copolymer ofN-vinyl-pyrrolidone and vinyl acetate to the content of nifedipine inthe composition is in the range 1:2 to 1:8.
 5. A composition accordingto claim 4 wherein said ratio of the polyvinylpyrrolidone or copolymerof N-vinylpyrrolidone and vinylacetate is in the range 1:2 to 1:5.
 6. Acomposition according to claim 1 wherein the nifedipine is present inamorphous form.
 7. A composition according to claim 1 wherein thepharmaceutically acceptable water soluble carrier has a particle size ofless than 250 μm.
 8. A composition according to claim 1 wherein thepharmaceutically acceptable water soluble carrier is lactose, sucrose ormannose or a mixture of two or more thereof.
 9. A composition accordingto claim 1 wherein the pharmaceutically acceptable carrier has a surfacearea of greater than 0.5 m² /g.
 10. A composition according to claim 1which is in the form of a solid unit dosage form.
 11. A compositionaccording to claim 10 wherein the solid unit dosage form is a tablet ora capsule.
 12. A process for the preparation of a pharmaceuticalcomposition which contains nifedipine as the active agent,polyvinylpyrrolidone or a copolymer of N-vinyl pyrrolidone and vinylacetate, and a pharmaceutically acceptable acrylic based polymer, theweight ratio of the polyvinylpyrrolidone or copolymer ofN-vinyl-pyrrolidone and vinylacetate to the content of nifedipine beingin the range of from 1:1 to 1:10 and the weight ratio of the acrylicbased polymer to the content of nifedipine being in the range of from1:4 to 1:20, which process comprises dissolving nifedipine,polyvinylpyrrolidone or the copolymer of N-vinylpyrrolidone and vinylacetate, and the pharmaceutically acceptable acrylic based polymer in asuitable solvent to form a solution, coating particles of a finelydivided pharmaceutically acceptable water soluble carrier which isinsoluble in the solvent with said solution and evaporating the solventfrom the coated carrier particles.
 13. A process according to claim 12wherein the water soluble carrier is coated with said solution instepwise fashion.
 14. A process according to claim 12 wherein thesolvent is a lower aliphatic alcohol, methylene chloride or chloroform.15. A process according to any one of claim 12 wherein the weight ratioof the polyvinylpyrrolidone or copolymer of N-vinylpyrrolidone and vinylacetate to the content of nifedipine is from 1:2 to 1:5.
 16. A processaccording to claim 12 wherein the coated particles are formed into asolid unit dosage form.
 17. A slow-release pharmaceutical compositionwhich comprises particles of a finely divided pharmaceuticallyacceptable water soluble carrier coated with a mixture of nifedipine inpredominantly amorphous form with polyvinylpyrrolidone or a copolymer ofN-vinylpyrrolidone and vinyl acetate, and a pharmaceutically acceptableacrylic based polymer, the weight ratio of the polyvinyl-pyrrolidone orcopolymer of N-vinylpyrrolidone and vinyl acetate to the content ofnifedipine being in the range of from 1: 1 to 1:10 and the weight ratioof the acrylic based polymer to the content of nifedipine being in therange of from 1:4 to 1:20.